Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.3(PAH):c.460T>C (p.Tyr154His)

CA229557

102685 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6d4b0dbf-3ec1-4b9d-9a22-949edf5d71fc

HGVS expressions

NM_000277.3:c.460T>C

NM_000277.3(PAH):c.460T>C (p.Tyr154His)

NC_000012.12:g.102866645A>G

CM000674.2:g.102866645A>G

NC_000012.11:g.103260423A>G

CM000674.1:g.103260423A>G

NC_000012.10:g.101784553A>G

NG_008690.1:g.55958T>C

NG_008690.2:g.96766T>C

NM_000277.1:c.460T>C

NM_000277.2:c.460T>C

NM_001354304.1:c.460T>C

ENST00000307000.7:c.445T>C

ENST00000549111.5:n.556T>C

ENST00000551988.5:n.530+10817T>C

ENST00000553106.5:c.460T>C

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH variant c.460T>C (p.Tyr154His) has been reported in three Chinese individuals with PHA deficiency (Phe levels >120 μM). The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl). All mutations identified were confirmed by analyzing parental DNA. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386). This variant was also reported in two other Chinese patients with undetermined PKU/MHP phenotype (PMID: 26503515, and PMID: 19915519). The PAH variant c.460T>C (p.Tyr154His) is absent from the gnomAD, ExAC, 1000 Genomes, and ESP population databases. In silico modeling, predictions support that this missense variant could have a deleterious effect on the PAH gene or gene product. This variant is predicted to be deleterious by SIFT, probably damaging by PolyPhen2- HumVar, and disease-causing by Mutation Taster. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4_Moderate.

PP4_Moderate

The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl) . All mutations identified in patients were confirmed by analyzing parental DNA. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PMID:16256386), and in two other Chinese patients with undetermined PKU/MHP phenotype (PMID: 26503515, and PMID: 19915519).

PubMed:19915519

PubMed:26503515

PP3

In silico modeling, predictions support a deleterious effect on the gene or gene product. This variant is predicted to be deleterious by SIFT, probably damaging by PolyPhen2- HumVar, and disease-causing by Mutation Taster.

PM2

The PAH variant c.460T>C (p.Tyr154His) is absent from the gnomAD, ExAC, 1000 Genomes, and ESP population databases.

PM3

The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl) . All mutations identified in patients were confirmed by analyzing parental DNA. (PM3 Points= 1*1=1) (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386) PM3 points awarded in total: 1.5

PubMed:26322415

PubMed:16256386

Approved on: 2019-12-22

Published on: 2019-12-22

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.